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bioRxiv · 10.1101/2024.09.05.611337

Zbtb38 inhibits apoptosis by transcriptionally regulating XIAP expression

Matsuda, E.·Shigeoka, T.·Nagaoka, H.·Nurulita, N. A.·Tada, S.·Ishida, Y.·Bessho, Y.
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Abstract

The X-linked inhibitor of apoptosis protein (XIAP) is a key suppressor of apoptosis, crucial for cellular differentiation, embryogenesis, and cancer progression. However, its upstream regulatory mechanisms remain poorly understood. Here, we demonstrate that the zinc finger transcription factor Zbtb38, a negative regulator of apoptosis, modulates XIAP expression in both loss- and gain-of-function experiments, irrespective of p53 expression. Notably, XIAP overexpression rescues the apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-associated apoptosis is at least partially XIAP-dependent. Mechanistically, Zbtb38 binds to E-box motifs within upstream regulatory regions of XIAP and activates its transcription. During embryonic stem (ES) cell differentiation and embryogenesis, Zbtb38 depletion increases apoptosis and reduces XIAP and Bcl-2 expression, underscoring their functional relevance in these processes. Analysis of human tumor datasets reveals a strong positive correlation between ZBTB38 and XIAP expression, with elevated ZBTB38 levels associated with high-grade malignancies. Furthermore, Zbtb38 knockdown induces apoptosis in cancer cells with reduced XIAP expression, regardless of p53 expression. Collectively, these findings uncover a novel Zbtb38-XIAP axis that regulates apoptosis during cellular differentiation, development, and oncogenesis, and highlight its therapeutic potential in XIAP-driven and p53-deficient tumors.

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Matsuda, E., Shigeoka, T., Nagaoka, H., Nurulita, N. A., Tada, S., Ishida, Y., Bessho, Y.. 2024-09-05. Zbtb38 inhibits apoptosis by transcriptionally regulating XIAP expression. https://doi.org/10.1101/2024.09.05.611337

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